Hypertension is a major health care burden in the United States, affecting 1 in 3 adults. Hypertension is associated with concomitant coronary artery disease with myocardial infarction (MI) and heart failure (HF). In this study, we will define how N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) protects cardiac structure and function in a mouse model of HF that will be induced in two models [angiotensin II (Ang II) hypertension- or permanent left anterior descending coronary ligation (LAD)]. We and others reported that Ang II-induced hypertension or LAD resulted in HF associated with cardiac structural remodeling and impaired function. Ac- SDKP is successively produced from thymosin ?4 (T?4) by two enzymes, meprin ? and prolyl oligopeptidase (POP). Circulating and tissue Ac-SDKP depends on the angiotensin converting enzyme (ACE) activity, since Ac- SDKP is mainly degraded by the N-terminal active side of ACE (ACE-N). ACEi are first-line drugs to treat HF. ACEi have strong side effects such as hypotension, cough, rash, angioneurotic edema, hyperkalemia, and dysgeusia, whereas Ac-SDKP has none, even at high dosages (up to 48 mg/kg/d). Also, Ac-SDKP is down- regulated in the myocardium of dogs and patients with chronic HF. Whether and how Ac-SDKP therapy could rescue hypertension- or LAD-induced cardiac complications remain to be elucidated. Increasing circulating Ac- SDKP not only inhibited fibrosis and mediators of inflammatory cell infiltration into the injured myocardium, but it also improved cardiac function in mice with LAD or hypertension (preliminary data). We have found that Ac- SDKP inhibits endoplasmic reticulum (ER) stress in cardiac fibroblasts in vitro and in mice with MI and restores phosphor-AKT in hypertensive hearts. Activation of ER stress is detrimental to the endothelium, cardiac fibroblasts, and cardiomyocytes. These findings set the scientific premise of this work, providing foundational work that Ac-SDKP represents a beneficial supplement to the existing cardiac pharmacotherapy. Our central hypothesis is that Ac-SDKP protects and potentiates cardiac protection against heart failure via the inhibition of ER stress. We propose to use the mouse model of heart failure induced by hypertension or LAD to address the following 2 two aims: ( 1) we will determine whether Ac-SDKP protects the heart and provides additional cardiac protective effects to ARBs, ACEi, or eplerenone in mice with MI or hypertension, ( 2) and we will demonstrate that Ac-SDKP improves cardiac function in mice with hypertension or LAD by inhibiting the detrimental ER stress via the PI3K/AKT pathway. A number of conditional and tissue-specific knockout female and male mice will be employed. A team with significant expertise is recruited for this project, which will apply a combination of state-of-the-art in vivo, cell and molecular techniques including measurements of cardiac remodeling and function by echocardiography in non-anesthetized mice and radiotelemetry, which can detect the blood pressure, the electrocardiogram, and the heart rate of conscious mice. These studies will help define the cause-effect relationship between Ac-SDKP and HF and its mechanism towards the protection from HF.